Cladribine

WARNING Cladribine injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received cladribine injection by continuous infusion at high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia). Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens. Acute nephrotoxicity has been observed with high doses of cladribine (4 to 9 times the recommended dose for Hairy Cell Leukemia), especially when given concomitantly with other nephrotoxic agents/therapies.

WARNINGS Due to increased risk of infection in the setting of immunosuppression with chemotherapy including cladribine, it is recommended not to administer live attenuated vaccines to patients receiving cladribine injection. Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine, especially at high doses. At initiation of treatment, most patients in the clinical studies had hematologic impairment as a manifestation of active Hairy Cell Leukemia. Following treatment with cladribine, further hematologic impairment occurred before recovery of peripheral blood counts began. During the first two weeks after treatment initiation, mean Platelet Count, ANC, and Hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively. The myelosuppressive effects of cladribine were most notable during the first month following treatment. Forty-four percent (44%) of patients received transfusions with RBCs and 14% received transfusions with platelets during Month 1. Careful hematologic monitoring, especially during the first 4 to 8 weeks after treatment with cladribine injection, is recommended (see PRECAUTIONS ). Fever (T ≥ 100°F) was associated with the use of cladribine in approximately two-thirds of patients (131/196) in the first month of therapy. Virtually all of these patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC ≤ 1000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤ 500). In a Phase I investigational study using cladribine in high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed. Thirty-one (31) poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (2 cases) received cladribine for 7 to 14 days prior to bone marrow transplantation. During infusion, 8 patients experienced gastrointestinal symptoms. While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients. Within 7 to 13 days after starting treatment with cladribine, 6 patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and 5 required dialysis. Several of these patients were also being treated with other medications having known nephrotoxic potential. Renal dysfunction was reversible in 2 of these patients. In the 4 patients whose renal function had not recovered at the time of death, autopsies were performed; in 2 of these, evidence of tubular damage was noted. Eleven (11) patients (35%) experienced delayed onset neurologic toxicity. In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis) of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with cladribine. Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease. Severe neurologic toxicity has also been noted with high doses of another drug in this class. Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation. Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens. In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there have been no reports of nephrologic toxicities. Serious (e.g. respiratory infection, pneumonia and viral skin infections), including fatal infections (e.g. sepsis) were reported (see ADVERSE REACTIONS ). Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were 8 deaths following treatment. Of these, 6 were of infectious etiology, including 3 pneumonias, and 2 occurred in the first month following cladribine therapy. Of the 8 deaths, 6 occurred in previously treated patients who were refractory to α interferon. Benzyl alcohol is a constituent of the recommended diluent for the 7-day infusion solution. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. (see DOSAGE AND ADMINISTRATION ) Pregnancy Category D Cladribine can cause fetal harm when administered to a pregnant woman. Although there is no evidence of teratogenicity in humans due to cladribine, other drugs which inhibit DNA synthesis have been reported to be teratogenic in humans. Cladribine is teratogenic in animals. Advise females of reproductive potential to use highly effective contraception during treatment with cladribine. If cladribine is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman. A significant increase in fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m 2 ) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3.0 mg/kg/day (9 mg/m 2 ). Fetal death and malformations were observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m 2 ). No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m 2 ) or in rabbits at 1.0 mg/kg/day (11.0 mg/m 2 ).

ADVERSE REACTIONS Clinical Trials Experience Adverse drug reactions reported by ≥ 1% of cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below. Adverse Drug Reactions in ≥ 1% of Patients Treated with Cladribine in HCL Clinical Trials System Organ Class Preferred Term Cladribine (n=576) % Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS ) Anemia 1 Febrile neutropenia 8 Psychiatric Disorders Anxiety 1 Insomnia 3 Nervous System Disorders Dizziness 6 Headache 14 Cardiac Disorders Tachycardia 2 Respiratory, Thoracic and Mediastinal Disorders Breath sounds abnormal 4 Cough 7 Dyspnea Dyspnea includes dyspnea, dyspnea exertional, and wheezing 5 Rales 1 Gastrointestinal Disorders Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper) 4 Constipation 4 Diarrhea 7 Flatulence 1 Nausea 22 Vomiting 9 Skin and Subcutaneous Tissue Disorders Ecchymosis 2 Hyperhidrosis 3 Petechiae 2 Pruritus 2 Rash Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous) 16 Musculoskeletal, Connective Tissue, and Bone Disorders Arthralgia 3 Myalgia 6 Pain Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity 6 General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS ) Administration site reaction Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction(erythema, edema, and pain) 11 Asthenia 6 Chills 2 Decreased appetite 8 Fatigue 31 Malaise 5 Muscular weakness 1 Edema peripheral 2 Pyrexia 33 Injury, Poisoning and Procedural Complications Contusion 1 The following safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff. In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Most non-hematologic adverse experiences were mild to moderate in severity. Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 × 10 6 /L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 × 10 9 /L) developed in 12% of patients, compared to 4% in whom it was noted initially. During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding cladribine therapy. During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics. (see WARNINGS and PRECAUTIONS ) Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/µL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/µL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/µL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear. Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as Day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts. The vast majority of rashes were mild. Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine. When used in other clinical settings the following ADRs were reported: bacteremia, cellulitis, localized infection, pneumonia, anemia, thrombocytopenia (with bleeding or petechiae), phlebitis, purpura, crepitations, localized edema and edema. For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS . Postmarketing Experience The following additional adverse reactions have been reported since the drug became commercially available. These adverse reactions have been reported primarily in patients who received multiple courses of cladribine injection: Infections and infestations: Septic shock. Opportunistic infections have occurred in the acute phase of treatment. Blood and lymphatic system disorders : Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia (including autoimmune hemolytic anemia), which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported. Immune system disorders : Hypersensitivity. Metabolism and nutrition disorders: Tumor lysis syndrome. Psychiatric disorders : Confusion (including disorientation). Hepatobiliary disorders : Reversible, generally mild increases in bilirubin (uncommon) and transaminases. Nervous System disorders : Depressed level of consciousness, neurological toxicity (including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis); however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens. Eye disorders : Conjunctivitis. Respiratory, thoracic and mediastinal disorders : Pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis); in most cases, an infectious etiology was identified. Skin and tissue disorders : Urticaria, hypereosinophilia; Stevens-Johnson. In isolated cases toxic epidermal necrolysis has been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes. Renal and urinary disorders: Renal failure (including renal failure acute, renal impairment).

<table width="75%"><caption>Adverse Drug Reactions in &#x2265; 1% of Patients Treated with Cladribine in HCL Clinical Trials</caption><col width="50%" align="left" valign="top"/><col width="50%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">System Organ Class Preferred Term </th><th styleCode="Rrule">Cladribine (n=576) % </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Blood and Lymphatic System Disorder </content>(see also sections <linkHtml href="#warnings"> WARNINGS </linkHtml>and <linkHtml href="#precautions"> PRECAUTIONS</linkHtml>) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Febrile neutropenia</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Cardiac Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tachycardia</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Breath sounds abnormal</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea <footnote ID="K1132">Dyspnea includes dyspnea, dyspnea exertional, and wheezing</footnote></td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rales</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain <footnote ID="K1158">Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper)</footnote></td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Flatulence</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">22</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Ecchymosis</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyperhidrosis</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Petechiae</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pruritus</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash <footnote ID="K1248">Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous)</footnote></td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal, Connective Tissue, and Bone Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain <footnote ID="K1282">Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity</footnote></td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions </content>(see also sections <linkHtml href="#warnings"> WARNINGS </linkHtml>and <linkHtml href="#precautions"> PRECAUTIONS</linkHtml>) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Administration site reaction <footnote ID="K1309">Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction(erythema, edema, and pain)</footnote></td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Chills</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">31</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Malaise</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Muscular weakness</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema peripheral</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">33</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Injury, Poisoning and Procedural Complications</content></td></tr><tr><td styleCode="Lrule Rrule"> Contusion</td><td styleCode="Rrule">1</td></tr></tbody></table>